S-B Kim

A multicenter, phase II trial of everolimus in locally advanced or metastatic thyroid cancer of all histologic subtypes

BACKGROUND This phase II study investigated the efficacy and safety of everolimus, an inhibitor of mammalian target of rapamycin (mTOR), in locally advanced or metastatic thyroid cancer. PATIENTS AND METHODS Patients with thyroid cancer of any histology that was resistant or not appropriate for (131)I received everolimus 10 mg daily orally until unacceptable toxicity or disease progression. The primary end point was disease control rate [partial response (PR) + stable response ≥12 weeks]. Secondary end points included response rates, clinical benefit (PD + durable stable disease (SD)], progression-free survival (PFS), overall survival, duration of response, and safety. RESULTS Thirty-eight of 40 enrolled patients were evaluable for efficacy. The disease control rate was 81% and two (5%) patients achieved objective response; their duration of response was 21+ and 24+ weeks. Stable disease (SD) and progressive disease was reported in 76% and 17% of patients, respectively. Seventeen (45%) patients showed durable SD (≥24 weeks) and clinical benefit was reported in 19 (50%) patients. Median PFS was 47 weeks [95% confidence interval (CI) 14.9-78.5]. Calcitonin, CEA, and thyroglobulin concentrations were ≥50% lower than baseline in three (30%) and four (44%) patients with medullary thyroid cancer and five (33%) patients with PTC, respectively. The most common treatment-related adverse events were mucositis (84%), anorexia (44%), and aspartate transaminase/alanine transaminase elevation (26%). CONCLUSIONS Everolimus had a limited activity with low response rate in locally advanced or metastatic thyroid cancer. Reasonable clinical benefit rate and safety profile may warrant further investigation. CLINICALTRIALSGOV NUMBER NCT01164176.

Abstract S1-03: Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer

Background The humanized monoclonal antibody (mAb) trastuzumab (H) + chemotherapy (chemo) prolongs disease-free survival (DFS) in patients (pts) with HER2-positive breast cancer (BC) in the adjuvant setting. Vascular endothelial growth factor (VEGF-A), one central regulator of angiogenesis, is a downstream target of HER2. Tumors overexpressing HER2 also overexpress VEGF-A and exhibit increased angiogenic potential. Combining H with the anti-VEGF-A mAb bevacizumab (B) significantly decreased tumor volume vs B or H alone in HER2-positive xenograft models and demonstrated efficacy in phase 2 studies. In the phase 3 AVEREL study in pts with HER2-positive metastatic BC, adding B to H + docetaxel (T) led to a non-significant increase in a duration of PFS and objective response rates. Chemo plus H±B is now explored in this large phase 3 trial to assess the impact of VEGF-A blockade on residual or micrometastatic disease in the adjuvant setting. Methods BETH (NCT00625898) is a randomized, phase 3, open-label study evaluating the addition of B to 2 different H-chemo regimens. Pts had centrally-confirmed HER2-positive BC (FISH+ and/or IHC 3+), ECOG PS 0-1, unilateral invasive breast adenocarcinoma, total mastectomy or lumpectomy, and LVEF ≥55%. Prior therapy with anthracyclines, taxanes, carboplatin (C), H or B for any malignancy or radiotherapy, chemo, and/or targeted therapy for the currently diagnosed BC were not permitted. Pts were stratified by center, hormone receptor status (ER and/or PR-positive, ER/PR-negative), and axillary lymph node status (0, 1-3, 4+) before inclusion into 1 of 2 chemo cohorts, and then randomized. All pts were recruited by investigators from the Translational Research in Oncology (TRIO/CIRG), the National Surgical Adjuvant Breast and Bowel Project (NSABP) or a group of independent sites. Cohort 1 (3231 pts) included pts receiving 6 cycles of TCH±B followed by H±B for 1 yr after the first dose. Cohort 2 (278 pts) included pts from some independent sites electing to use anthracycline-based therapy and these pts received 3 cycles of TH±B followed by 3 cycles of 5-fluorouracil, epirubicin, cyclophosphamide followed by H±B to complete 1 yr of treatment. T was given at 8 mg/kg IV loading dose, 6 mg/kg IV q3w thereafter; B was given at 15 mg/kg IV q3w. The primary endpoint is invasive DFS (IDFS) for B-containing vs. non-B-containing regimens. Secondary endpoints are IDFS within chemo cohorts, DFS, overall survival, recurrence-free interval (RFI), distant RFI, safety including specific cardiac assessments, and the identification of predictive biomarkers for B. The sample size was determined to test the hypothesis of interest, both in the faster accruing cohort and overall. With 3509 pts enrolled, the trial will have 85% power to detect a HR of 0.70 favoring the addition of B overall, irrespective of chemo regimen. With ∼3000 pts in the faster-accruing cohort, the study will have 80% power to detect a hazard ratio (HR) of 0.70 at a 2-sided alpha of 0.05. Median duration of follow-up will be 36 months in Jun 13, cut-off date of the primary analysis. Initial efficacy, safety, and plasma marker analyses will be reported. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-03.

Abstract S1-07: A phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X, JBCRG-04)

Background Patients (pts) with pathologic residual invasive disease after neoadjuvant chemotherapy (NAC) have an intermediate or high-risk for relapse. It is not clear whether further systemic chemotherapy is beneficial for these pts. CREATE-X is a multicenter open-label randomized phase III trial evaluating this major clinical issue using capecitabine (X) in pts without pCR after NAC (UMIN000000843). We have shown previously that the addition of 8 cycles of X to standard adjuvant therapy is feasible and well tolerated (Ohtani S, et al. SABCS2013#P3-12-03). We report the first efficacy results from a pre-planned interim analysis after 2-year follow-up. Methods Pts with HER2-negative residual invasive cancer after anthracycline- and/or taxane-containing NAC were randomized to standard treatment (RT, hormone therapy (HT) as appropriate) with or without 8 cycles of X (1250 mg/m2 bid, days1–14,q3w). Pts with hormone receptor (HR)-positive disease received HT either with or after X, according to each center9s prespecified standard practice. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS), safety, and cost-effectiveness. It was originally planned to enroll 450 pts in each arm in order to detect a HR 0.74 improvement in the X arm with 80% power and a two-sided 5% significance level. We planned one interim analysis of DFS at 2-years after all pts enrolled using Lan-DeMets alpha spending function method (O9Brein-Fleming type). Results Between Feb 2007 and Jul 2012, 910 pts were randomized, with 455 pts to receive X. The full analysis consisted of 902 pts who matched the inclusion criteria. Baseline characteristics were well balanced. The median age was 48 years in both arms; 63.5% were HR-positive. In the investigational arm, HT was given with X concurrently in 200 pts and after X in 24 pts. The relative dose intensity of X was 78.8%. At the time of the interim analysis, DFS events were confirmed in 81 (18.8%) in the investigational arm and 109 (24.7%) in the standard arm, and OS events were 28 (6.5%) and 41 (9.3%), respectively. On Kaplan-Meier analysis, 2-year DFS was 87.3% for the arm with X and 80.5% for no X (HR:0.688, 98.66%CI: 0.479-0.989, log-rank P=0.001). The tendency for improvement of OS by adding X was also confirmed; 2-year OS was 96.2% and 93.9%, respectively (HR: 0.658, 95%CI: 0.407-1.065, log-rank P=0.086). In the experimental arm with X, grade 3/4 toxicities included HFS (11%), neutropenia (9%), diarrhea (3%), and fatigue (1%); all were controllable. No SAE was related to X administration. Because the study met the primary endpoint, an independent data monitoring committee recommended discontinuation of the study. Conclusions: The clinical utility of X in the adjuvant setting for breast cancer pts has been proven to improve the prognosis based on the pathological response-guided strategy. Tolerability was consistent with the established safety profile of X in mBC. The benefit to risk balance of the addition of 8 cycles of X to standard adjuvant therapy seems to be satisfied. This evidence might allow the development of personalized individualized treatment based on the response to primary systemic therapy. Citation Format: Toi M, Lee S-J, Lee ES, Ohtani S, Im Y-H, Im S-A, Park B-W, Kim S-B, Yanagita Y, Takao S, Ohno S, Aogi K, Iwata H, Kim A, Sasano H, Yokota I, Ohashi Y, Masuda N. A phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X, JBCRG-04). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S1-07.

S5-7: A Phase 2, Randomized, Open-Label, Study of Neratinib (HKI-272) vs Lapatinib Plus Capecitabine for 2nd/3rd-Line Treatment of HER2+ Locally Advanced or Metastatic Breast Cancer.

Background: Neratinib (N), an irreversible pan-tyrosine kinase inhibitor (TKI), with activity against HER1, -2 and -4, has shown antitumor activity in patients (pts) with HER2+ breast cancer (BC). Lapatinib (L), a reversible HER1 and -2 TKI is approved in combination with capecitabine (C) for treatment of pts with HER2+ advanced or metastatic BC who had prior therapy. Materials and Methods: This phase 2, randomized, open-label study evaluated safety and efficacy of N 240 mg/day vs L 1,250 mg/day plus C 2,000 mg/m2/day (14 days/21 day cycle) in pts with HER2+ locally advanced or metastatic BC. Eligible pts had: ≤2 prior trastuzumab regimens, prior taxane treatment, and no prior anthracycline treatment with cumulative dose >400 mg/m2 doxorubicin, >800 mg/m2 epirubicin, or >equivalent dose of other anthracycline. Primary endpoint was progression-free survival (PFS; investigator-assessed); secondary endpoints included safety, overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR;% pts with complete response, partial response, or stable disease ≥24 wks). Tumor assessments were every 6 wks for the first 48 wks, then every 12 wks until progressive disease (PD; RECIST 1.0) or initiation of new anticancer therapy. Results: Overall, 117 pts were randomized to N and 116 to L plus C (LC). Mean age (SD; range) was 53.9 y (10.3; 28–79); 60% were White, 34% Asian, and 6% other. Prior treatments included: trastuzumab (229 pts: 168 metastatic or locally advanced, 51 adjuvant, 10 neoadjuvant), taxanes (230 pts), and anthracycline (156 pts). Median treatment duration (range) was 126.5 days (1-636) for N and 201 days (13-622) for LC. Median relative dose intensity (actual/expected exposure) for N was 100%. As of data cutoff, 84% had discontinued treatment; 65% from PD (N 63%, LC 67%), 9% for adverse events (AEs; N 7%, LC 11%). In the ITT cohort, for N and LC, respectively, median PFS (95% CI) was 4.5 mo (3.1−5.7) and 6.8 mo (5.9−8.2; P = 0.091; hazard ratio = 1.3 [95% CI, 1.0−1.8]); median OS (95% CI) was 19.4 mo (19.4−22.2; 41 deaths) and 19.0 mo (16.9-NA; 35 deaths; P = 0.180); ORR (95% CI) was 29% (21-38) and 41% (32-50; P = 0.067); CBR (95% CI) was 44% (35-54) and 64% (54-73; P = 0.003). Most common drug-related treatment-emergent AEs (TEAEs; any grade) were diarrhea (N 84%, LC 67%), nausea (34%, 38%), palmar-plantar erythrodysesthesia (PPE; 5%, 63%), and rash (18%, 34%); for grade ≥3, diarrhea (28%, 10%) and PPE (0, 14%). Dose reductions/discontinuations from diarrhea occurred in 13/3 pts on N, and 15/7 pts on LC. Study deaths for N and LC, respectively, included: 36 pts (31%) and 32 pts (28%) from PD; 5 pts (4%) and 3 pts (3%) from AEs unrelated to study drug. Discussion: In this setting of pts less heavily pre-treated than in the pivotal LC trial, single agent N demonstrated high anti-tumor activity (ORR 29%), confirming results from prior N phase 2 trials. N alone did not appear to be as effective as LC. No unexpected TEAEs were observed; N was well tolerated in pts with HER2+ locally advanced or metastatic BC; while diarrhea was more frequent on N than LC, it was manageable with antidiarrheals and did not lead to more treatment discontinuations. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S5-7.

PD01-02: Randomized Phase II Study of Dasatinib vs Placebo in Addition to Exemestane in Advanced ER/PR-Positive Breast Cancer [BMS CA180-261 Study].

Background: Src-family kinases (SFKs) are involved in estrogen receptor (ER) and progesterone receptor (PgR) signaling pathways, in resistance to hormonal therapy, and in osteoclast function. Dasatinib is a potent oral inhibitor of SFKs and other kinases, but single-agent activity in advanced breast cancer (ABC) is limited. Biomarkers may identify patient subsets with increased benefit. In this Phase II study, the combination of dasatinib with exemestane was evaluated in patients (pts) with ER+ and/or PgR+ ABC resistant to a nonsteroidal aromatase inhibitor (NSAI). Methods: In a randomized double-blind Phase II trial (CA180-261), 157 patients (pts) with ECOG performance status of 0–1, measurable or evaluable disease, and progression (PD) during, or within 1 year after adjuvant, treatment with an NSAI were stratified by symptomatic bone metastasis (SBM) and other factors, and assigned 1:1 to receive dasatinib (100 mg daily) or matched placebo in combination with exemestane (25 mg daily). Progression-free survival (PFS) was the primary endpoint and clinical benefit (CBR; partial response+stable disease ≥24 wks) the key secondary endpoint. The study was designed for 80% power to detect a hazard ratio (HR) of 0.67 between arms, corresponding to median PFS increase from 4 to 6 months using 1-sided α=0.1. Archival tumor samples for biomarker analysis were collected. Patient-reported pain score and a measure of bone lysis (urinary N-telopeptide, uNTX) were collected serially in pts with SBM. Results: Planned analysis was performed after 119 events (PD or death) were recorded, at which time 129 pts had discontinued study treatment. Overall PFS comparison was non-significant (HR=0.86; 1-sided p=0.148), with median PFS of 16 weeks (95% CI 12, 18) in the placebo arm and 18 weeks (95% CI 15,24) in the dasatinib arm. Estimated free-from-progression rate at 24 weeks was 33% in placebo and 43% in the dasatinib arm. Pts with SBM, 40% of study population, had improved PFS on the dasatinib arm (HR=0.68, 1-sided p=0.094). Preliminary CBR at this analysis (31 of 38 censored pts continue on study) was higher in the dasatinib arm. Expected dasatinib-related toxicities were observed, including pleural effusion [23% (5% Gr≥3) in dasatinib vs 1% (0 Gr≥3) in placebo] and diarrhea [25% (1% Gr≥3) vs 1% (0 Gr≥3)]. Musculoskeletal adverse events (AEs) were comparable between arms, but fatigue or asthenia [37% (4% Gr≥3) vs 20% (0 Gr≥3)], skin AEs [28% (1% Gr≥3) vs 11% (0 Gr≥3)] and headache [22% (3% Gr≥3) vs 9% (0 Gr≥3)] were more common in dasatinib arm. Dose interruption or reduction was more frequent for dasatinib compared to placebo. Biomarker analyses are in progress. Conclusion: PFS difference (HR=0.82) was not significant in overall study population, but higher CBR in the dasatinib arm and higher PFS in pts with SBM (HR=0.68) suggests that dasatinib has efficacy in a subset. The safety profile was consistent with dasatinib experience; AEs, including pleural effusion and diarrhea, were more common with dasatinib as compared with placebo. Updated efficacy and biomarker analyses will be presented. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD01-02.

Abstract S5-05: Trastuzumab emtansine improves overall survival versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer: Final overall survival results from the phase 3 TH3RESA study

Introduction The phase 3, randomized, open-label, TH3RESA study (BO25734/TDM4997g; NCT01419197) compared trastuzumab emtansine (T-DM1) with treatment of physician9s choice (TPC) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), previously treated with a taxane (any setting), and both trastuzumab and lapatinib (advanced setting). Progression-free survival (PFS) and overall survival (OS) were co-primary endpoints. Results of the primary PFS analysis and the first interim OS analysis showed significantly improved PFS with T-DM1 compared with TPC and a trend for improved OS, although the stopping boundary was not reached (Krop IE, et al. Lancet Oncol 2014). The incidence of grade ≥3 adverse events (AEs) was lower with T-DM1 vs TPC (32% vs 43%). Here we report the results from the second interim analysis of OS from TH3RESA, which will serve as the final OS results. Methods Eligible patients were randomized 2:1 to receive T-DM1 (3.6 mg/kg IV every 3 weeks) or TPC. The pre-specified OS efficacy stopping boundary was an observed hazard ratio (HR) Results From Sept 14, 2011 to Nov 19, 2012, 602 patients were randomized to T-DM1 (n=404) or TPC (n=198). TPC comprised HER2-directed regimens (83%) and single-agent chemotherapy (17%). At the data cutoff for this analysis (Feb 13, 2015), 93 patients (47%) had crossed over from TPC to T-DM1. At a median follow-up time of 30.5 months, OS was significantly longer with T-DM1 vs TPC (median OS 22.7 vs 15.8 months; HR=0.68 [95% CI, 0.54–0.85; p=0.0007]) and these results crossed the OS efficacy stopping boundary. A sensitivity analysis, in which patients were censored when they switched from TPC to T-DM1, also showed an OS benefit with T-DM1 vs TPC (median 22.7 vs 15.6 months; HR=0.58 [95% CI: 0.43–0.77; p=0.0002]). The OS benefit was consistently observed across subgroups defined by age, visceral involvement, hormone receptor status, number of prior regimens, and TPC type. The T-DM1 group had nearly twice the mean exposure to the planned study treatment as the TPC group (7.93 vs 4.08 months). In treated patients, the incidence of grade ≥3 AEs was 40.0% and 47.3% in the T-DM1 and TPC arms, respectively. Grade ≥3 AEs occurring in ≥3% of either treatment arm were neutropenia (T-DM1, 2.5%; TPC, 15.8%), febrile neutropenia (T-DM1, 0.2%; TPC, 3.8%), thrombocytopenia (T-DM1, 6.0%; TPC, 2.7%), anemia (T-DM1, 3.5%; TPC, 3.3%), dyspnea (T-DM1, 2.5%; TPC, 3.8%), diarrhea (T-DM1, 0.7%; TPC, 4.3%), and asthenia (T-DM1, 1.0%; TPC, 3.3%). Conclusions In this population of patients with advanced breast cancer who previously received a taxane, trastuzumab, and lapatinib, treatment with T-DM1 resulted in a statistically significant and clinically meaningful improvement in OS compared with TPC. A lower incidence of grade ≥3 AEs was observed with T-DM1 and its safety profile was consistent with previous studies. These data further solidify the role of T-DM1 in the treatment of previously treated HER2-positive advanced breast cancer. Citation Format: Wildiers H, Kim S-B, Gonzalez-Martin A, LoRusso PM, Ferrero J-M, Yu R, Smitt M, Krop I. Trastuzumab emtansine improves overall survival versus treatment of physician9s choice in patients with previously treated HER2-positive metastatic breast cancer: Final overall survival results from the phase 3 TH3RESA study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S5-05.

P1-12-09: Safety and Efficacy of Neratinib in Combination with Capecitabine in Patients with ErbB2-Positive Breast Cancer.

Background: Neratinib (HKI-272) is an irreversible pan-ErbB receptor tyrosine kinase inhibitor that has shown antitumor activity in patients with ErbB2+ breast cancer. Capecitabine has demonstrated efficacy and tolerability in combination with lapatinib, a reversible dual ErbB1/ErbB2 kinase inhibitor, in patients with ErbB2+ advanced breast cancer. The current study evaluated the safety and clinical activity of neratinib in combination with capecitabine. Methods: In part 1 of this open-label, phase 1/2 study, the maximum tolerated dose (MTD) of neratinib in combination with capecitabine was determined in adults with advanced solid tumors. Part 2 of the study further evaluated the safety and clinical activity of neratinib plus capecitabine at the MTD in adults with confirmed ErbB2+ metastatic or locally advanced breast cancer (ECOG Performance Status of 0–2). Eligible patients had received prior taxane treatment and ≥1 prior trastuzumab-containing regimen for ≥6 weeks for metastatic or locally advanced disease. The primary endpoint of part 2 was objective response rate (ORR); tumor responses were assessed by investigators using modified RECIST version 1.0 guidelines every 6 weeks. Results: In part 1 (n = 33), the MTD was determined to be neratinib 240 mg/day plus capecitabine 750 mg/m 2 twice daily on Days 1 to 14 of each 21-day cycle. In part 2, as of April 2011, 72 female patients (median age of 52 years [range, 33–79 years]) with ErbB2+ breast cancer were enrolled and treated at the MTD; 7 patients had prior lapatinib exposure and all had prior trastuzumab and taxane exposure. As of the snapshot date, 56% of patients at the MTD were still participating in the study. The most common drug-related adverse events (AEs) in part 2 were diarrhea (89%), palmar-plantar erythrodysesthesia (57%), nausea (33%), vomiting (26%), and decreased appetite (22%). Grade 3/4 drug-related AEs in ≥5% of patients were diarrhea (25%) and palmar-plantar erythrodysesthesia (13%). Eight patients withdrew from part 2 due to AEs, including 4 who withdrew due to diarrhea. Dose interruptions of neratinib and capecitabine, respectively, due to AEs were required by 19 and 29 patients; dose reductions due to AEs were required by 8 and 22 patients. As of June 2010 (interim analysis), 22 patients were evaluable for efficacy in part 2 of the study. Of these 22 patients, 11 achieved a partial response for an ORR of 50%. An additional 2 patients maintained stable disease for ≥24 weeks, resulting in a clinical benefit rate of 59%, and 8 patients had stable disease for Conclusions: The results of this study indicate that neratinib combined with capecitabine is tolerable and has promising antitumor activity in patients with ErbB2+ metastatic or locally advanced breast cancer pretreated with trastuzumab. This study supports further evaluation of this combination in ErbB2+ breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-09.

Abstract OT2-6-11: PENELOPE: Phase III study evaluating palbociclib (PD-0332991), a cyclin-dependent kinase (CDK) 4/6 inhibitor in patients with hormone-receptor-positive, HER2-normal primary breast cancer with high relapse risk after neoadjuvant chemotherapy (GBG-78/BIG1-13)

Background: About one third of hormone-receptor (HR)-positive, HER2-normal breast cancer (BC) patients with residual disease after neoadjuvant chemotherapy (NACT) have a substantial risk of relapse. Those patients can be identified using validated clinical-pathologic stage–estrogen/grade (CPS-EG) scoring system. Palbociclib is an oral, highly selective inhibitor of CDK4/6 kinase activity that prevents cellular DNA synthesis by inhibiting cell cycle progression. Luminal tumors have been shown to be sensitive to palbociclib. In a phase 2 study, palbocilcib extended PFS in combination with letrozole as first-line hormonal treatment for advanced BC. In addition, it has shown single agent activity in patients with multiply relapsed hormone positive ABC. Methods: PENELOPE (NCT01864746) is a prospective, international, multicenter, randomized, double-blind, placebo-controlled, phase 3 study aiming to demonstrate that 1 year of adjuvant treatment with palbociclib, in addition to standard anti-hormonal therapy, provides a superior invasive disease-free survival (iDFS) and acceptable safety profile compared to placebo in women with HR-positive/HER2-normal early BC who did not obtain a pathological complete response (pCR) after taxane-containing NACT and are at high risk of relapse (CPS-EG score ≥3). After completion of NACT and adequate surgery and radiotherapy, 800 patients will receive standard adjuvant endocrine treatment (5years) and will be randomized (1:1) to 13 cycles of palbociclib 125mg daily or matching placebo on d1-21 in a 28d cycle. Randomization will be dynamic and patients will be stratified by histological lymph node status at surgery (ypN 0-1 vs ypN2-3), age at first diagnosis ( 50 yrs), Ki-67 (>15% vs 2 points), global region of participating site (Eur vs N.America vs RoW). Patients will be followed until any invasive local, regional or distant recurrence, diagnosis of secondary malignancy, unacceptable toxicity, withdrawal of consent or study termination. Primary objective is to compare iDFS for palbociclib vs placebo. Secondary objectives are iDFS excluding second non-breast cancers, overall, distant disease-free and locoregional recurrence-free survival, iDFS per treatment arm in luminal-B tumors, compliance and safety, patient reported outcomes, health economics, correlations between drug exposure and efficacy/safety findings. Further objectives are translational and aim to identify scores/markers for their prognostic value and predictive information on efficacy/safety of palbociclib in this specific setting. Results: Recruitment is planned to start in Oct 2013 at 200-250 sites in 11 countries and continue for 3years. Conclusion: PENELOPE will study whether palbociclib is an effective treatment with a sufficiently favorable safety profile for patients with high risk of recurrence and high CPS-EG score after NACT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-11.

Abstract P5-18-26: Confirmatory overall survival (OS) analysis of CLEOPATRA: a randomized, double-blind, placebo-controlled Phase III study with pertuzumab (P), trastuzumab (T), and docetaxel (D) in patients (pts) with HER2-positive first-line (1L) metastatic breast cancer (MBC)

Background: In CLEOPATRA, 808 pts with HER2-positive 1L MBC were randomized to treatment with placebo (Pla)+T+D or P+T+D. The primary endpoint of independently reviewed progression-free survival was significantly improved with P+T+D vs Pla+T+D (HR = 0.62; P Methods: This interim OS analysis was performed applying the Lan-DeMets α-spending function with the O9Brien-Fleming (OBF) stopping boundary to maintain the overall Type I error at 5%. Based on the number of OS events observed, the OBF boundary for statistical significance at this analysis was P≤0.0138. The log-rank test, stratified by prior treatment status and geographic region, was used to compare OS between arms in the intention-to-treat population. The Kaplan-Meier approach was used to estimate the median OS in both arms; a stratified Cox proportional hazard model was used to estimate HR and 95% CIs. Subgroup analyses of OS were performed for the stratification factors and other key baseline characteristics. Results: At the time of this analysis, median follow-up was 30 mths and 267 deaths (69% of planned events for the final analysis) had occurred. The results showed a statistically significant improvement in OS in favor of P+T+D (HR = 0.66; 95% CI, 0.52–0.84; P = 0.0008). This HR represents a 34% reduction in the risk of death. The analysis achieved statistical significance and is therefore considered the confirmatory OS analysis. The median OS was 37.6 mths in the Pla arm and has not yet been reached in the P arm. The treatment effect was generally consistent in predefined subgroups based on baseline variables and stratification factors, including: prior (neo)adjuvant therapy (HR = 0.66; 95% CI, 0.46–0.94); no prior (neo)adjuvant therapy (HR = 0.66; 95% CI, 0.47–0.93); prior (neo)adjuvant T (HR = 0.68; 95% CI, 0.30–1.55); hormone receptor-negative disease (HR = 0.57; 95% CI, 0.41–0.79); and hormone receptor-positive disease (HR = 0.73; 95% CI, 0.50–1.06). Kaplan-Meier estimates of OS rates show survival benefit with P+T+D at 1, 2, and 3 yrs. The majority of pts received anti-cancer therapy after discontinuation of study treatment (64% Pla arm, 56% P arm). Subsequent therapy with HER2-directed agents (T, lapatinib, T emtansine) was balanced between arms. Causes of death remained unchanged from the first interim OS analysis, with the most common cause being progressive disease. Adverse events leading to death were rare and balanced between arms. Conclusions: Treatment of pts with HER2-positive 1L MBC with P+T+D compared with Pla+T+D was associated with an improvement in OS, which was both statistically significant and clinically meaningful. These results show that combined HER2 blockade and chemotherapy using the P+T+D regimen can be considered a standard of care for pts with HER2-positive MBC in the 1L setting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-18-26.

Short term results from GHRH analogue use in pre-menopausal breast cancer in Korea

BACKGROUND Hormone receptor-positive, pre-menopausal breast cancer patients can be treated by chemotherapy and/or ovarian suppression therapy. We reported our experience of gonadotropin-releasing hormone analogue plus tamoxifen (GnRHa+T) or adriamycin and cyclophosphamide (AC) followed by tamoxifen (AC-->T) in pre-menopausal women with hormone-response, node-negative breast cancer. METHODS We retrospectively reviewed the records of 587 pre-menopausal women with hormone-responsive, node-negative breast cancer. Of these, 269 were treated with adriamycin and cyclophosphamide (AC) followed by tamoxifen (AC-->T), and 318 were treated with gonadotropin-releasing hormone analogue plus tamoxifen (GnRHa+T). Among them, 151 patients were treated by goserelin acetate 3.6 mg/kg and 125 patients were treated by leuprorelin acetate 3.75 mg/kg every 28 days subcutaneously. FINDINGS At a median follow-up time of 30 months, eight patients had relapsed and three had died. DFS did not differ between the AC-->T and GnRHa+T groups. Of the three deaths, two were not related to breast cancer. The third patient, in the AC-->T group, died because of brain metastasis. GnRHa+T treatment had no effect on blood profile and did not cause the development of detrimental symptoms but decreased bone mineral density. The efficacy of leuprorelin was similar to that of goserelin. INTERPRETATION GnRHa+T treatment can be an alternative treatment option in pre-menopausal women with endocrine-responsive, node-negative, breast cancer patients. The efficacy and tolerability of leuprorelin were similar to that of goserelin.